Age-related macular degeneration (AMD) is a complex disease where multiple nongenetic and genetic risk factors lead to disease development in an age-related fashion. Aging and cigarette smoking are the clearest examples of nongenetic risk factors, and both have been linked to elevated levels of oxidative stress. Genetic risk factors include a set of variant alleles for genes in the alternative complement pathway, among others. One of the fundamental objectives in AMD research is to understand how nongenetic factors are integrated with the genetic basis of this disease. The epigenetic regulation of the genome is currently thought to be the molecular mechanism through which nongenetic factors have an effect. In this application, we propose to study the age-related epigenetic regulation of wild type alleles of manganese superoxide dismutase (SOD2) and complement factor H (CFH), two genes whose variant alleles are associated with the risk of AMD. SOD2 is the major source of cytosolic hydrogen peroxide which leads to oxidative stress in the retinal pigment epithelium (RPE), and its expression is epigenetically regulated. CFH is a major inhibitor of the alternative complement pathway, whose expression is regulated by oxidative stress at the transcriptional level and epigenetically through miR-146a at the translational level. We hypothesize that nongenetic mechanisms regulating the expression of the wild type alleles of SOD2 and CFH lead to an alteration of protein concentration, which is similar to changes of function for the gene products of the mutant alleles. The significance of this work rests in a hypothesis which integrates genetics, environmental effects, and aging. Approaching the pathogenesis of AMD in this fashion may lead to new clinical approaches for better management or even prevention of the disease. PUBLIC HEALTH RELEVANCE: This proposal focuses on the epigenetics of age-related changes in the regulation of superoxide dismutase (SOD2) and complement factor H (CFH) expression in the mouse and human retinal pigment epithelium. The goal is to identify mechanisms that integrate our understanding of the genetic and environmental basis of age-related macular degeneration (AMD). The significance of this work is to better understand how genetic and environmental influences work together in disease pathogenesis. This work will eventually lead to the development of better approaches for risk management and treatment of AMD.